Safety and efficacy of lorlatinib against ALK-driven refractory or relapsed neuroblastoma
Authors: Yujin Suk, Sheila K. Singh
Journal: Cell Reports Medicine (2023)

We spotlight the promising preliminary findings reported by Goldsmith et al. of a phase 1 first-in-child study showcasing the safety and efficacy of lorlatinib against treatment-refractory or relapsed ALK-driven neuroblastoma.1Goldsmith K.C. Park J.R. Kayser K. Malvar J. Chi Y.Y. Groshen S.G. Villablanca J.G. Krytska K. Lai L.M. Acharya P.T. et al.Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.Nat. Med. 2023; Crossref Scopus (1) Google Scholar We spotlight the promising preliminary findings reported by Goldsmith et al. of a phase 1 first-in-child study showcasing the safety and efficacy of lorlatinib against treatment-refractory or relapsed ALK-driven neuroblastoma.1Goldsmith K.C. Park J.R. Kayser K. Malvar J. Chi Y.Y. Groshen S.G. Villablanca J.G. Krytska K. Lai L.M. Acharya P.T. et al.Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.Nat. Med. 2023; Crossref Scopus (1) Google Scholar Neuroblastoma is the most common extracranial solid tumor occurring in pediatric patients, with approximately 90% of the tumors being diagnosed in children who are <10 years of age.1Goldsmith K.C. Park J.R. Kayser K. Malvar J. Chi Y.Y. Groshen S.G. Villablanca J.G. Krytska K. Lai L.M. Acharya P.T. et al.Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.Nat. Med. 2023; Crossref Scopus (1) Google Scholar,2Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, , Weiss W.A., Nat. Rev. Dis. Primers 2016, 2, 16078.Google Scholar,3Johnsen J.I. Dyberg C. Wickström M. Neuroblastoma-A neural crest Derived Embryonal Malignancy.Front. Mol. Neurosci. 2019; 12: 9Crossref PubMed Scopus (0) Google Scholar There is a significant range in clinical features and prognosis that stems from the breadth of sites from which the tumors may arise in and the ability of some tumors to spontaneously regress, highlighting the importance of risk stratification and risk-adapted therapy regimens most suitable for each patient. For this reason, patients diagnosed with low- to intermediate-risk tumors are currently eligible for therapy de-escalation trials, while research is underway for novel therapeutic modalities for patients in the high-risk category that are facing metastatic, relapsed, or treatment-refractory tumors.4Qiu B. Matthay K.K. Advancing therapy for neuroblastoma.Nat. Rev. Clin. Oncol. 2022; 19: 515-533Crossref Scopus (26) Google Scholar To identify drivers of oncogenesis and, in effect, targetable pathways, researchers have over the past decade undertaken genome-wide association and whole-genome screening studies that identified ALK as the most common somatically mutated gene in neuroblastoma.5Trigg R.M. Turner S.D. ALK in neuroblastoma: Biological and therapeutic implications.Cancers. 2018; 10: 113Crossref PubMed Scopus (0) Google Scholar,6Wulf A.M. Moreno M.M. Paka C. Rampasekova A. Liu K.J. Defining pathological Activities of ALK in neuroblastoma, a neural Crest-Derived cancer.Int. J. Mol. Sci. 2021; 22: 11718Crossref Scopus (6) Google Scholar Gain-of-function mutations in the ALK oncogene make up half of all familial neuroblastoma cases. In all cases, ALK mutations are thought to lead to auto- and transphosphorylation of ALK receptors, resulting in increased mitogenic signaling involving the PI3K/AKT, PLCγ, STAT3/STAT5, and RAS/MAPK pathways.5Trigg R.M. Turner S.D. ALK in neuroblastoma: Biological and therapeutic implications.Cancers. 2018; 10: 113Crossref PubMed Scopus (0) Google Scholar ALK mutations have implications in treatment resistance and recurrence and frequently co-occur with MYCN amplifications, another alteration that is directly linked with poor outcomes.1Goldsmith K.C. Park J.R. Kayser K. Malvar J. Chi Y.Y. Groshen S.G. Villablanca J.G. Krytska K. Lai L.M. Acharya P.T. et al.Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.Nat. Med. 2023; Crossref Scopus (1) Google Scholar Previous studies have identified treatment-refractory or relapsed neuroblastomas to harbor increased levels of ALK somatic mutations through either emergence of novel mutations or increased levels of mutant allele frequencies of pre-existing alterations as compared with their primary tumors.4Qiu B. Matthay K.K. Advancing therapy for neuroblastoma.Nat. Rev. Clin. Oncol. 2022; 19: 515-533Crossref Scopus (26) Google Scholar,7Zafar A. Wang W. Liu G. Wang X. Xian W. McKeon F. Foster J. Zhou J. Zhang R. Molecular targeting therapies for neuroblastoma: Progress and challenges.Med. Res. Rev. 2021; 41: 961-1021Crossref Scopus (85) Google Scholar,8Schleiermacher G. Javanmardi N. Bernard V. Leroy Q. Cappo J. Rio Frio T. Pierron G. Lapouble E. Combaret V. Speleman F. et al.Emergence of new ALK mutations at relapse of neuroblastoma.J. Clin. Oncol. 2014; 32: 2727-2734Crossref PubMed Scopus (143) Google Scholar Taken together, there is undoubtedly a significant rationale for targeting ALK in recurrent neuroblastoma. Despite the revolutionizing effect that ATP-competitive tyrosine kinase inhibitors (TKIs) targeting oncogenes such as ALK/Met/ROS1 were able to have on non-small cell lung carcinoma (NSCLC) patients harboring ALK translocations, first-generation ALK TKIs such as crizotinib were unable to yield significant efficacy for neuroblastoma patients.9Peng L. Zhu L. Sun Y. Stebbing J. Selvaggi G. Zhang Y. Yu Z. Targeting ALK Rearrangements in NSCLC: Current state of the Art.Front. Oncol. 2022; 12863461Google Scholar,10Pottier C. Fresnais M. Gilon M. Jérusalem G. Longuespée R. Sounni N.E. Tyrosine kinase inhibitors in cancer: Breakthrough and challenges of targeted therapy.Cancers. 2020; 12: 731Crossref PubMed Scopus (0) Google Scholar This, in part, may have been due to differences in targeting full-length mutated ALK in neuroblastoma compared with ALK fusion proteins in other cancers such as NSCLC, anaplastic large cell lymphoma, and inflammatory myofibroblastic tumors. Lorlatinib is the third-generation iteration of ALK-targeted small molecule inhibitors. The small and compact macrocyclic formation shows increased metabolic stability, low frequency of P-glycoprotein-mediated efflux in vitro, and greater blood-brain barrier permeability than previous generations. Lorlatinib was primarily developed to address the emergent ALK mutations that arose in response to first- or second-generation ALK TKIs in NSCLC. Lorlatinib preclinically showed efficacy against F1174L, F1245C, and R1275Q hotspot mutations in neuroblastoma patient xenograft models; in clinical trials, only R1275Q-mutated tumors were responsive to crizotinib and ceritinib therapy. The New Approaches to Neuroblastoma Therapy (NANT) Consortium ran the NANT2015-02 first-in-child phase 1 study (NCT03107988) testing lorlatinib with and without chemotherapy for patients older than 12 months with measurable refractory or relapsed high-risk neuroblastoma.1Goldsmith K.C. Park J.R. Kayser K. Malvar J. Chi Y.Y. Groshen S.G. Villablanca J.G. Krytska K. Lai L.M. Acharya P.T. et al.Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.Nat. Med. 2023; Crossref Scopus (1) Google Scholar While the trial was ongoing, the investigators reported on 3 cohorts that had already met previously specified primary endpoints of safety, pharmacokinetics, and recommended phase 2 doses. The first cohort (A1) of pediatric and adolescent patients (12 months to <18 years, n = 25) were given lorlatinib as single agent; the second cohort (A2) of adult patients (>18 years, n = 15) were also given lorlatinib as single agent, and the third cohort (B2) treated pediatric and adolescent patients (<18 years, n = 9) with lorlatinib in combination with topotecan and cyclophosphamide. All ALK hotspot mutations were represented: F1174 C/L at 51%, R1275Q at 33%, and F1245Y/L at 12%. One patient had ALK amplification, and one patient had a pathologic D1276_R1279 activating mutation. Pharmacokinetic analyses were observed at expected values (increasing with increasing dose levels), and steady-state values were comparable with those found in lung cancer patients. The response rate (complete/partial/minor) in cohort A1 was 30%, cohort A2 was 67%, and cohort B2 was 63%. Interestingly, the one patient with the germline ALK mutation had sustained response at the lowest lorlatinib dose, indicating ALK-targeted therapy may be a highly effective avenue for germline mutations. The most common grade 1–4 adverse events were hypertriglyceridemia (90%), hypercholesterolemia (79%), and weight gain (87%). Grade 1–2 peripheral limb edema occurred mainly in patients >18 years of age (47%) rather than in patients <18 years of age (4%). Patients who received topotecan and cyclophosphamide also experienced the expected hematologic toxicities associated with chemotherapy but experienced no overlapping side effects. Only 9% of patients required dose reduction, and all adverse events were resolved with either dose hold, reduction, or discontinuation. With the given findings demonstrating the safety, tolerability, and response to treatment, lorlatinib is being rapidly translated into the active Children's Oncology Group phase 3 trial (NCT03126916) as an amendment to replace crizotinib for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. The same is underway for the European phase 3 trial in collaboration with the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN). As the authors describe, for future studies, it will be extremely useful to determine the mechanism behind the significantly lower response rates in relapsed younger patients who also harbor MYCN amplifications. As ALK mutations and MYCN amplifications frequently co-occur together, there is an urgent need for rationally developed combinatorial therapeutic strategies. This trial shows some preliminary support for combining chemotherapy and lorlatinib for a greater probability of response in these subsets of patients, but more targeted therapies directed against MYCN or its downstream pathways may be warranted. Furthermore, development of fourth-generation ALK TKIs such as TPX-0131 and NVL-655 with greater ALK-binding capabilities and blood-brain permeability provides additional avenues that may be suitable for patients facing ALK-driven neuroblastoma and warrants preclinical modeling in parallel with lorlatinib. Lastly, with its blood-brain-permeable formulation (in effect also causing the neurological adverse events reported in this study), it would be important to investigate this drug as a potential treatment or preventative measure for brain metastases that are found in relapsed neuroblastoma patients, especially those exiting GD2 antibody therapy. S.K.S. is a scientific advisor for Century Therapeutics Inc., and her role in the company has been reviewed and is supported by McMaster University.